The present invention relates to alpa2-adrenergic receptor agonist nitrooxyderivatives and to their use for the treatment of ocular diseases in particular for the treatment of high intraocular pressure and glaucoma.
Glaucoma occurs in about 2% of all population over the age of 40 and may be asymptomatic for years before progressing to rapid loss of vision.
Glaucoma is primarily classified as open-angle, closed-angle, or congenital, and further classified as primary and secondary. Glaucoma is treated with a variety of pharmacological and surgical approaches. In cases where glaucoma is associated with ocular hypertension, pharmacological treatment comprises adrenergic agonists (epinephrine, dipevefrin, apraclonidine), cholinergic agonists (pilocarpine), beta blockers (betaxolol, levobunolol, timolol), carbonic anhydrase inhibitors (acetazolamide, clorzilamide) or more recently, prostaglandin analogues (latanoprost, bimatoprost) and alpha adrenergic agonists (brimonidine, apraclonidine). These pharmacological approaches help to restore the IOP to a normotensive state either by inhibiting the production of aqueous humor by the ciliary body, or facilitating aqueous humor outflow across the trabecular meshwork. In particular alpha-adrenergic agonists, such as brimonidine and apraclonidine, control IOP by reducing the production of aqueous humor as well as enhancing uveoscleral outflow.
Alpha2-adrenergic receptor agonists are also used for the treatment of ocular hypertension and optic neuropathies both in monotherapy and as adjunctive therapy to beta-blockers. They are also used for the prophylactic treatment of acute pressure rises (i.e. before and after argon laser trabeculoplasty, cataract surgery, vitrectomy, peripheral iridotomy, capsulotomy). Their activity is due mainly to the activation of alpha2-adrenergic receptors in the eye; such activation leads to reduction of acqueous humor production and increase in uveoscleral outflow. (Curr Opin Ophtalmol 1997, 8(2); 42-49)
It is known that optical ophthalmic solutions containing alpha2-adrenergic receptor agonists are absorbed systemically and can produce side-effects including systemic hypotension, decreased heart rate, dry mouth, lid retraction, conjunctiva blanching, hyperaemia, burning, uveitis, tachyphilaxis, posterior segment vasoconstriction, topical allergy-like syndrome, increased pupil diameter, depression, anxiety, fatigue, nausea. (Hoyng and van Beek, Drugs, 59: 411-434 (2000), Surv Ophthalmol 1996, 41 Suppl 1: S19-26)
As described above, agents commonly used to treat glaucoma may cause adverse effects. Thus, there is a need for selective alpha2-adrenergic receptor agonists that are both safe and effective in the treatment of ocular diseases and in particular glaucoma.
It has been surprisingly found that alpha2-adrenergic receptor agonists nitrooxyderivatives of formula (I) have a significantly improved overall profile as compared to native compounds with respect to both pharmacological activity and enhanced tolerability.